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GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation
Hong Soon Kang, … , Raja Jothi, Anton M. Jetten
Hong Soon Kang, … , Raja Jothi, Anton M. Jetten
Published October 30, 2017
Citation Information: J Clin Invest. 2017;127(12):e94417. https://doi.org/10.1172/JCI94417.
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Research Article Endocrinology

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

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Abstract

Deficiency in Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) in humans is associated with the development of congenital hypothyroidism. However, the functions of GLIS3 in the thyroid gland and the mechanism by which GLIS3 dysfunction causes hypothyroidism are unknown. In the current study, we demonstrate that GLIS3 acts downstream of thyroid-stimulating hormone (TSH) and TSH receptor (TSHR) and is indispensable for TSH/TSHR-mediated proliferation of thyroid follicular cells and biosynthesis of thyroid hormone. Using ChIP-Seq and promoter analysis, we demonstrate that GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, both of which showed enhanced GLIS3 binding at their promoters. The repression of cell proliferation of GLIS3-deficient thyroid follicular cells was due to the inhibition of TSH-mediated activation of the mTOR complex 1/ribosomal protein S6 (mTORC1/RPS6) pathway as well as the reduced expression of several cell division–related genes regulated directly by GLIS3. Consequently, GLIS3 deficiency in a murine model prevented the development of goiter as well as the induction of inflammatory and fibrotic genes during chronic elevation of circulating TSH. Our study identifies GLIS3 as a key regulator of TSH/TSHR-mediated thyroid hormone biosynthesis and proliferation of thyroid follicular cells and uncovers a mechanism by which GLIS3 deficiency causes neonatal hypothyroidism and prevents goiter development.

Authors

Hong Soon Kang, Dhirendra Kumar, Grace Liao, Kristin Lichti-Kaiser, Kevin Gerrish, Xiao-Hui Liao, Samuel Refetoff, Raja Jothi, Anton M. Jetten

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Figure 5

Loss of GLIS3 function decreases the expression of several genes required for TH biosynthesis.

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Loss of GLIS3 function decreases the expression of several genes require...
(A) Relative gene expression in thyroids from WT and Glis3KO mice fed either ND or LID was analyzed by QRT-PCR analysis. n ≥ 4 for each group. (B) Protein lysates obtained from thyroids of WT and Glis3KO mice fed either ND or LID were examined by Western blot analysis with antibodies against NIS and PAX8. GAPDH was used as a loading control. (C) Representative images of sections of WT and Glis3KO thyroids immunoassayed with antibodies against NIS (green), WGA (red), and DAPI. Scale bar: 50 μm. (D) The relative intensity of NIS immunostaining was analyzed with ImageJ (NIH) and plotted. n ≥ 2 for each group. (E) PCCl3-pIND20-Glis3 cells stably expressing Glis3 under the control of a Dox-inducible promoter were treated with or without Dox in the presence or absence of TSH and insulin (Ins). The expression of Glis3 and Nis was examined by QRT-PCR. (F) PCCl3 cells stably expressing Glis3 shRNA under the control of a Dox-inducible promoter to knock down Glis3 expression were treated with or without Dox in the presence or absence of TSH and insulin. The expression of Glis3 and Nis was examined by QRT-PCR. Data in E and F are derived from triplicate samples and representative of 2 independent experiments. Data are shown as mean ± SEM. *P < 0.05; **P < 0.001; ***P < 0.0001, Student’s t test. rGlis3 and rNis refer to rat genes.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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